Facile and enantiospecific syntheses of (6 S,7 R)-6-chloro-7-BENZYLOXY-, (7 S)-halo-, and (7 S)-hydroxy-cocaine and natural (-)-cocaine from d -(-)-ribose

Article abstract of DOI:10.1021/ol2009686

First syntheses of C6,7 and C7 enantiopure cocaine analogues were achieved from d-(-)-ribose via a trans-acetonide controlled endo-selective intramolecular nitrone-alkene cycloaddition (INAC) as the key step. This synthetic scheme allows practical preparation of cocaine analogues for bioevaluation as potential candidates for the treatment of cocaine addiction and as potential conjugates for immunotherapy.

Full text of DOI:10.1021/ol2009686

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2916–2919
Facile and Enantiospecific Syntheses of
(6S,7R)-6-Chloro-7-benzyloxy-, (7S)-Halo-,
and (7S)-Hydroxy-cocaine and Natural
(ꢀ)-Cocaine from D-(ꢀ)-Ribose
Tony K. M. Shing* and King H. So
Department of Chemistry and Center of Novel Functional Molecules, The Chinese
University of Hong Kong, Shatin, NT, Hong Kong, China
tonyshing@cuhk.edu.hk
Received April 13, 2011
ABSTRACT
First syntheses of C6,7 and C7 enantiopure cocaine analogues were achieved from D-(ꢀ)-ribose via a trans-acetonide controlled endo-selective
intramolecular nitrone-alkene cycloaddition (INAC) as the key step. This synthetic scheme allows practical preparation of cocaine analogues for
bioevaluation as potential candidates for the treatment of cocaine addiction and as potential conjugates for immunotherapy.
Notorious tropane alkaloid (ꢀ)-cocaine (1)1 is a power-
ful stimulant of the central nervous system, and its neuro-
nal reinforcing properties are attributable to its inhibition
of dopamine reuptake.2 Cocaine abuse has been a pivotal
medical problem in the world, and 1.6 million current users
by age 12 are estimated in the U.S.3 Furthermore, cocaine
abuse has indirectly enhanced the spread of human im-
munodeficiency virus infection and drug-resistant tube-
rculcosis.4 To date, aneffective medication totreat patients
addicted to cocaine is still elusive and research effort on the
synthesis of cocaine analogues for bioevaluation must
continue. Tremendous studies have been made on C2
and C3 cocaine analogues, but C6 and C7 analogues are
relatively underexplored.5,6 This is because C2 and C3
analogues were readily derived from (ꢀ)-cocaine (1)
whereas access to C6 and C7 analogues must rely on total
synthesis. Existing C6 and C7 analogues were synthesized
€
as racemates by modifying the classical Willstatter synth-
esis of cocaine.5a,b Resolution is required to produce
enantiopure analogues which hampers the development
of a pharmacotherapy. Recently, Davis et al. described
the asymmetric synthesis of cocaine C1-alkyl analogues
using essentially an asymmetric variant of the Tufariello
(5) For some reports of synthesis of cocaine analogues, see: (a)
racemic 6β- and 7β-methoxylated cocaine: Simoni, D.; Stoelwinder, J.;
Kozikowski, A. P.; Johnson, K. M.; Bergmann, J. S.; Ball, R. G. J. Med.
Chem. 1993, 36, 3975–3977. (b) racemic 6β- and 7β-hydroxylated
cocaine: Kozikowski, A. P.; Simoni, D.; Manfredini, S.; Roberti, M.;
Stoelwinder, J. Tetrahedron Lett. 1996, 37, 5333–5336. (c) enantiopure
C1-alkyl cocaine analogues: Davis, F. A.; Theddu, N.; Edupuganti, R.
Org. Lett. 2010, 12, 4118–4121.
(6) For some reports of synthesis of C2 and C3 tropane analogues,
see: (a) Carroll, F. I.; Blough, B. E.; Mascarella, S. W.; Navarro, H. A.;
Eaton, J. B.; Lukas, R. J.; Damaj, M. I. J. Med. Chem. 2010, 53, 8345–
8353. (b) Stehouwer, J. S.; Jarkas, N.; Zeng, F.; Voll, R. J.; Williams, L.;
Camp, V. M.; Malveaux, E. J.; Votaw, J. R.; Howell, L.; Owens, M. J.;
Goodman, M. M. J. Med. Chem. 2008, 51, 7788–7799. (c) Zhang, S.;
Izenwasser, S.; Wade, D.; Xu, L.; Trudell, M. L. Bioorg. Med. Chem.
2006, 14, 7943–7952. (d) Bois, F.; Baldwin, R. M.; Kula, N. S.; Baldes-
sarini, R. J.; Innis, R. B.; Tamagnan, G. Bioorg. Med. Chem. Lett. 2004,
14, 2117–2120. (e) Zhao, L.; Johnson, K. M.; Zhang, M.; Flippen-
Anderson, J.; Kozikowski, A. P. J. Med. Chem. 2000, 43, 3283–3294.
(1) Simoni, D.; Rondanin, R.; Roberti, M. In Targets in Heterocyclic
Systems; Attanasi, O. A., Spinelli, D., Eds.; Italian Society of Chemistry:
Roma, 1999; Vol. 3, pp 147ꢀ183.
(2) (a) Ritz, M. C.; Lamb, R. J.; Goldberg, S. R.; Kuhar, M. J.
Science 1987, 237, 1219–1223. (b) Kuhar, M. J.; Ritz, M. C.; Boja, J. W.
Trends Neurosci. 1991, 14, 299–302. (c) Koob, G. F.; Bloom, F. E.
Science 1988, 242, 715–723.
(3) Substance Abuse and Mental Health Services Administration.
(2010). Results from the 2009 National Survey on Drug Use and Health:
Vol. I. Page 1. Summary of National Findings (Office of Applied Studies,
NSDUH Series H-38A, HHS Publication No. SMA 10ꢀ4586Findings),
Rockville, MD. http://oas.samhsa.gov/NSDUH/2k9NSDUH/2k9ResultsP.pdf.
(4) Herman, B. H.; Elkashef, A.; Vocci, F. Drug Discovery Today:
Therapeutic Strategies 2005, 2, 87–92.
r
10.1021/ol2009686
Published on Web 05/05/2011
2011 American Chemical Society

synthesis of cocaine.5c Enantiospecific syntheses of C6 and
C7 cocaine analogues have not been addressed in the
literature, and herein, we report facile and efficient synth-
eses of (6S,7R)-6-chloro-7-benzyloxy-, (7S)-hydroxy-, (7S)-
chloro-, (7S)-methanesulfonyloxy-, and (7S)-iodo-cocaine
analogues from inexpensive D-(ꢀ)-ribose (2) via a trans-
acetonide controlled endo-selective intramolecular nitrone-
alkene cycloaddition (INAC) reaction7 as the key step. The
cocaine framework in these analogues was corroborated by
conversion into natural (ꢀ)-cocaine (1).8
its E-geometry. Regioselective acid hydrolysis of the term-
inal acetonide in 6 followed by glycol cleavage oxidation12
gave aldehyde 7, which condensated with MeNHOH to
generate nitrone 4. INAC reaction produced a mixture of
inseparable seven-membered endo-cycloadduct 3 and six-
memberedexo-cycloadduct 8 ina ratio of20:1, respectively
(1H NMR spectral analysis). It is noteworthy that an R,
β-unsaturated ester as the dipolarophile did not induce the
formation of an endo-cycloadduct anticipated from an
electronic effect,13 thereby confirming the steric control
of the endo-mode of cycloaddition is attributable to the
trans-acetonide group. This mixture of inseparable cy-
cloadducts 3 and 8 was then subjected to TFA hydrolysis
to yield a mixture of diols 9 and 10, respectively, separable
on column chromatography. The structures of 9 and 10
were confirmed by X-ray crystallography.14
Our retrosynthesis is based on the construction of a
seven-membered bridged carbocycle 3 via a key endo-
selective INAC reaction7 of nitrone 4, which is readily
prepared from D-(ꢀ)-ribose (2) (Scheme 1). Our previous
work7 has indicated that hept-6-enoses containing a 3,
4-trans-acetonide direct the INAC reactions to give endo
cycloadducts (cycloheptanes) exclusively. The stereochem-
istry of the ring junction is also controlled by the trans-
acetonide whereby the newly formed CꢀN bond is anti to
the C3 alkoxy group. Hence, nitrone 4 is expected to give
the bridged cycloheptane 3 and the methoxycarbonyl
group must be in the β-face as shown, a consequence of
the stereospecificity of the pericyclic reaction (E-alkene to
β-methoxycarbony group). The C1, C2, and C3 stereo-
centers in the cocaine analogues would therefore be estab-
lished in one synthetic operation, i.e. the INAC reaction.
Scheme 2. Syntheses of Cocaine Analogues 13, 14, 15, and (ꢀ)-
Cocaine (1)
Scheme 1. Retrosynthesis of Cocaine Analogues
The syntheses of cocaine analogues and (ꢀ)-cocaine (1)
are shown in Scheme 2. D-(ꢀ)-Ribose (2) was transformed
into alkene 5 in three steps involving aqueous indium
allylation,9 acetonation, and benzylation as reported
previously.10 Cross metathesis of 5 with methyl acrylate
catalyzed by a second generation Grubbs catalyst11 af-
forded R,β-unsaturated ester 6 in an excellent yield. The
large coupling constant (J = 15.7 Hz) of the two alkene
signals observed in the 1H NMR spectrum of 6 confirmed
(7) (a) Shing, T. K. M.; Wong, W. F.; Ikeno, T.; Yamada, T. Chem.;
Eur. J. 2009, 15, 2693–2707. (b) Shing, T. K. M.; Wong, A. W. F.; Ikeno,
T.; Yamada, T. J. Org. Chem. 2006, 71, 3253–3263.
(8) For previous asymmetric syntheses of cocaine, see: (a) Lin, R.;
Castells, J.; Rapoport, H. J. Org. Chem. 1998, 63, 4069–4078. (b) Lee,
J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000, 65, 4773–4775. (c) Mans,
D. M.; Pearson, W. H. Org. Lett. 2004, 6, 3305–3308. (d) Davis, F. A.;
Theddu, N.; Edupuganti, R. Org. Lett. 2010, 12, 4118–4121. (e) Cheng,
G.; Wang, X.; Zhu, R.; Shao, C.; Xu, J.; Hu, Y. J. Org. Chem. 2011, 76,
2694–2700.
With the diol 9 in hand, it was regioselectively esterified
with Tf2O and the monotriflate ester formed was then
treated withbasic MeOH to giveepoxide11. Raney-Nickel
(9) Prenner, R. H.; Schmid, B. W. Liebigs Ann. Chem. 1994, 73–78.
(10) Shing, T. K. M.; Wong, W. F.; Ikeno, T.; Yamada, T. Org. Lett.
2007, 9, 207–209.
(11) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H.
J. Am. Chem. Soc. 2000, 122, 3783–3784.
(12) Zhong, Y. L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622–2624.
(13) Our studies showed that the INAC of nitrone 22, bearing an R,
β-unsaturated ester and a cis-acetonide, gave exo-cycloadduct 23 exclu-
sively. The regio- and stereochemistry was confirmed by X-ray crystal-
lographic analysis of its benzoate 24 (CCDC 681970).
Org. Lett., Vol. 13, No. 11, 2011
2917

mediated hydrogenolysis of 11 yielded azetidine-diol 12.
The NꢀO bond of 11 was first cleaved to give the corre-
sponding amine, which opened the epoxy ring at C6 to
afford bicyclo[4.1.1] diol 12.15 The formation of a bicyclo-
[4.1.1] skeleton instead of the tropane structure (by attack-
ing C5) might be rationalized by Baldwin’s rule,16 in which
the 4-Exo-Tet cyclization (leading to a bicyclo[4.1.1]
skeleton) is more favored than the 5-Endo-Tet cyclization
(leading to a tropane skeleton). This azetidine-diol 12 was
then transformed into (6S,7R)-6-chloro-7-benzyloxy co-
caine (13) by a one-pot reaction of benzoylation and
mesylation in excellent overall yield. The C3-OH of 12
was first benzoylated, and the remaining free C5-OH in 16
was then mesylated (Scheme 3). As the aza-bridge is anti to
the C5-OMs group, neighboring-group participation
would assist the mesylate ion in 17 to dissociate easily,
giving ammonium ion 18.17 Then the nucleophilic chloride
ion attacked the C6R position of 18 to furnish (6S)-
chloride 13. The release of ring strain from the bicyclo-
[4.1.1] skeleton to the tropane ring is probably the driving
force for the attack at C6 instead of C5.
Thus, (6S,7R)-6-chloro-7-benzyloxy cocaine was obtained
for the first time in 12 steps with 26% overall yield from
D-(ꢀ)-ribose (2). Hydrogenolysis of 13 in the presence of
Raney-Nickel provided the first synthesis of another co-
caine analogue, (7S)-hydroxy cocaine (14) (13 steps, 19%
from 2). This alcohol 14 is the 7-epimer of the known (7R)-
1
hydroxy cocaine.5b,18 The H NMR spectrum of (7R)-
hydroxy cocaine (obtained from Prof. K. D. Janda) was
found to be very similar to that of 14, except for their H7
splitting pattern (dd in (7R)-hydroxy-cocaine and ddd in
our 14), which is in good agreement with the observations
on its structurally related compounds in the literature.5a
The third (ꢀ)-cocaine analogue, (7S)-chloro-cocaine (15)
(14 steps, 17% from 2), was synthesized by reacting 14 with
MsClat 70°C in a sealedtube. The mesylate19formedwas
displaced readily by a chloride ion at an elevated tempera-
ture to give 15 (Scheme 4). The presence of a chlorine atom
in 15 was again confirmed by mass spectrometry. From the
1H NMR spectrum of 15, the S-stereochemistry of Cl7 was
assigned by comparing its coupling constant (J1,7 = 6.4 Hz)
with that in structurally related compounds.5a,b The reten-
tion of configuration upon the displacement reaction of
(7S)-mesylate 19 by a chloride ion might be rationalized
by the proposed mechanism shown in Scheme 4. The
neighboring-group participation of the aza-bridge encour-
aged the dissociation of the mesylate in 19 to form ammo-
nium ion 20 and the chloride ion then attacked from the
C7R-face of 20, furnishing (7S)-chloro-cocaine (15).
Scheme 3. Proposed Mechanism from 12 to 13
Scheme 4. Proposed Mechanism from 14 to 15
The presence of a chlorine atom in 13 was confirmed by
mass spectrometry. The tropane skeleton in 13 was as-
1
signed by 1Hꢀ H connectivities from the 2D COSY NMR
spectrum and the strong NOE correlation between H6 and
H7 supported the S-stereochemistry of the chloride at C6.
The cocaine framework in these analogues was corro-
borated by the transformation of chloride 15 into natural
(ꢀ)-cocaine (1) via Raney-Nickel mediated hydrogenoly-
sis. The physical and spectral data of synthetic (ꢀ)-cocaine
(1) were in full accordance with those reported in the
literature.8a Thus natural (ꢀ)-cocaine (1) was also synthe-
sized in 15 steps from D-(ꢀ)-ribose (2) with 13% overall
yield. The overall yield of this synthetic scheme was found
to be higher than the recently reported (þ)-cocaine synth-
esis (9% overall yield from methyl 4-nitrobutanoate) by
Davis et al.5c,19 The lower cost of our starting material
(14) Please refer to Supporting Information for X-ray structures of 9
(CCDC 737152) and 10 (CCDC 752110) .
(15) The structure of azetidine-diol 12 was confirmed by X-ray
crystallographic analysis of its tribenzoate derivative (CCDC 798275).
Its preparation is described in the Supporting Information.
(16) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.
(17) The existence of such ammonium ion 18 was supported by the
racemization of acetate product upon acetylation of L-2R-tropanol as
reported by Archer et al.; see: Archer, S.; Lewis, T. R.; Bell, M. R.;
Schulenberg, J. W. J. Am. Chem. Soc. 1961, 83, 2386–2387.
(18) The (7R)-hydroxy cocaine had been used to synthesize haptens
for immunopharmacotherapy in cocaine abuse; see: Ino, A.; Dickerson,
T. J.; Janda, K. D. Bioorg. Med. Chem. Lett. 2007, 17, 4280–4283.
(19) (a) Simoneau, B.; Brassard, P. Tetrahedron 1988, 44, 1015–1022.
(b) Davis, F. A.; Zhang, H.; Lee, S. H. Org. Lett. 2001, 3, 759–762.
2918
Org. Lett., Vol. 13, No. 11, 2011

ensures that our avenue is more economical and our
synthetic route has great potential for synthesis of other
(ꢀ)-cocaine analogues.
21 is believed to be reactive toward radical reactions hence
forming even more (ꢀ)-cocaine analogues.
To conclude, we have provided a facile, practical, and
highyieldingaccesstofive(ꢀ)-cocaineanalogues, (6S,7R)-
6-chloro-7-benzyloxy-, (7S)-hydroxy-, (7S)-chloro-, (7S)-
methanesulfonyloxy-, and (7S)-iodo-cocaine, in 12ꢀ15
steps with 14ꢀ26% overall yields from inexpensive D-ri-
bose. Halo-analogues 13, 15, and 21 are also valuable
synthetic intermediates which can be elaborated via ionic
or radical reactions into a wide variety of cocaine analo-
gues. Research in this direction is in progress.
Scheme 5. Synthesis of (ꢀ)-Cocaine Analogues 19 and 21
Acknowledgment. This work was financially supported
by a CUHK direct grant and Center of Novel Functional
Molecules. We thank Professor K. D. Janda (The Scripps
Research Institute) for kindly providing the H NMR
spectrum of (7R)-hydroxy cocaine for comparison.
For example, when alcohol 14 was mesylated at room
temperature, (7S)-methanesulfonyloxy cocaine (19) in-
stead of chloride 15 was isolated (Scheme 5). This mesylate
19 readily undergoes displacement reactions with nucleo-
philes. When 19 reacted with the iodide anion, (7S)-iodo-
cocaine (21) was formed. The retention of configuration of
the iodide in 21 was also rationalized by neighboring-
group participation as described previously. This iodide
1
Supporting Information Available. Experimental pro-
cedures and product characterization. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 11, 2011
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